Side chain removal process



United States Patent SlDE CHAIN REMOVAL PROCESS William E. Weesner,Dayton, Ohio, assignor to Monsanto Chemical Company, St. Louis, Mo., acorporation of Delaware No Drawing. Application September 3, 1954 SerialNo. 454,225

Claims. (Cl. 260-3405) I This invention relates to a process for removalof the fi-carboxyethyl side chain of certain polyhydrophenanthrenecompounds referred to hereinafter as keto-acids.

1,8a dimethyl-A -polyhydrophenanthren-Z-ones ,of the structure CH3 CH3where R is a substituted or unsubstituted 4-carbon atom chain forming aG-membered fused ring as described, are employed in the total synthesisof steroidal compounds of the cyclopentanopolyhydrophenanthrene series.In the intermediary steps which provide for Ring A a ,B-carboxyethylgroup is introduced to the 1-position of said 1,8a-dimethyl A1050)polyhydrophenanthren 2 ones. By so doing a new asymmetric center isintroduced which yields therefore a one hundred percent increase in thenumber of geometric isomers. These isomers are generically termedketoacids, half of which are termed a-keto-acids and the other, theirepimers, p-keto-acids. As those skilled in the art are well aware butonly one of these keto-acid isomers is useful in synthesizing aparticular steroid and, thusly, means have been constantly sought toconvert the other to a useful product in the synthesis.

In accordance with this invention it has been found that the alkalimetal salt of a keto-acid of the structure noooorhomwhere R is asubstituted or unsubstituted 4-carbon atom chain forming a 6-memberedfused ring as described, in the form of a melt upon subjection to apyrolyzing temperature at a pressure below atmospheric is readilyconverted to the corresponding LSa-dimethyl-Apolyhydrophenanthren-2-one.

In the process of this invention the pyrolyzing temperature generallywill be in the range of from about 200 C. to about 350 C., butpreferably in the range of from about 250 C. to about 320 C. Althoughany pressure below atmospheric is operable, it is preferred thatpressures below about 100 mm. of mercury be employed.

The keto-acid salt starting materials are prepared by methods fullydescribed in the literature as is the preparation of the parentketo-acid compounds, e. g. I. A. C. S., 74, pp. 4223 if, and I. A. C.S., 75, p. 4110. As illlustrative of the keto-acid salt startingmaterials of this invention are the sodium, potassium and lithium saltsof 2,846,447 Patented Aug. 5, 1958 e CC dodecahydrophenanthren-Z-one;

1,8a dimethyl 1 (B-carboxyethyl) A dodecahy drophenanthren-2,8-dione;

1,8a dimethyl l (B-carboxyethyl) 8 bromo A dodecahydrophenanthren-Z-one;

1,821 dimethyl 1 (,B-carboxyethyl) 8 chloro Adodecahydrophenanthren-Z-one;

1,8a dimethyl 1 (fl-carboxyethyl) 6,7 dihydroxy- A-dodecahydrophenanthren-Z-one acetonide; and like 1,8a dimethyl 1s-carboxyethyl) A polyhydrophenanthren-2-ones.

As illustrative of the process of this invention is the following:

Example 1 To a suitable reaction vessel equipped with a take-01f tubeconnected through a vacuum adapter to a receiving vessel is addedapproximately 10 parts by weight the sodium salt of the a-isomer ofdl-anti-trans-l,Sa-dimethyl- 1 (fi-carboxyethyl) 6,7 dihydroxy Adodecahydrophenanthren-Z-one acetonide. [This salt is prepared byadmixing the theoretical quantity of 0.1 N sodium hydroxide with thea-isomer of dl-anti-trans-1,8a-dimethyl l (fi-carboxyethyl) 6,7dihydroxy A dodecahydrophenanthren-Z-one acetonide until completesolution occurs, followed by evaporating to dryness and grinding the dryproduct.] The contents of the reaction vessel are melted and heated inan oil bath over a range of about 250-313 C. at 0.3-0.4 mm. of mercurypressure. After a period of 50 minutes approximately 4.6 parts by weightof distillate is collected which distillate is taken up with a mixtureof diethyl ether and petroleum ether and crystallized therefrom. Thewhite crystalline substance so obtained isdl-anti-trans-l,8a-dimethyl-6,7- dihydroxy-A-dodecahydrophenanthren-2-one acetonide. The yield based upon thedistillate is 56.9% of theory.

Similarly also colorless oily dl-anti-trans-1,8a-dimethyl- A-decahydrophenanthren-Z-one is obtained by the pyrolysis of thepotassium salt of the a-isomer of dl-antitrans-1,8-dimethyl l (6carboxyethyl) A -decahydrophenanthien-Z-one.

In the process of this invention either crude or pure keto-acid in theform of its alkali metal salt may be employed. A particular aspect ofthis invention is admixing a keto-acid salt with an alkali metal salt ofa hydrocarbon mono-carboxylic acid, i. e. a compound of the formulaRC0.0H Where R is a hydrocarbon radical such as methyl, ethyl, propyl,butyl, hexyl, octyl, decyl, benzyl, phenethyl, phenpropyl, phenyl,tolyl, ethylphenyl, indenyl, naphthyl, etc., and subjecting a melt ofthe mixture to a pyrolyzing temperature employing a pressure belowatmospheric. ,As illustrative of this embodiment is the following:

Example I] To a suitable reaction vessel equipped with a take-01f tubeconnected through a vacuum adapter 'to a receiving vessel is addedapproximately 4.9 parts by weight of the sodium salt of the a-isorner ofdl-anti-trans-l,8a-dimethyll-(p-carboxyethyl) 6,7 dihydroxy-A-dodecahydrophenanthren-Z-one acetonide and approximately 50 parts byweight of sodium phenyl acetate and intimately mixed. This mixture(melting point about 200 C.) is heated in an old bath over a range ofabout 280300 C. under a pressure of about 0.15 to 0.3 mm. of mercury.After a period of about two hours approximately 3.8 parts by weight ofdistillate is collected which distillate is taken Example III To a'suitable reaction vessel equipped with atake-oif tube connected througha vacuum adapterto a receiving vessel is added approximately 50 parts byweight of potassium acetate and approximately 50 parts by weight ofsodium acetate and the mixture melted. To'the melt is addedapproximately parts by weight 'of thesodium salt of the tit-isomer ofdl-anti-trans-1,8a-dimethyl-1-;(;8- carboxyethyl)-A-decahydrophenanthren 2 one. The mix is then heated over a range ofabout 260310 C. under'a pressure of about 2 mm. of mercury. After aperiod of about 45 minutes the collected distillate is taken up withchloroform, Washed with water, dried and then evaporated. Approximately4 parts by weight of a yellow oil consisting chiefly of colorless oilydl-anti-trans-LSadimethyl-h -decahydrophenanthren 2 one is obtained.

Example IV To a suitable reaction vessel equipped with a take-off tubeconnected through a vacuum adapted to a recovery vessel is addedapproximately 7.5 parts by weight of the sodium salt of the ,B-isomer ofdl-anti-trans-l,8a-di.methyll-(B carboxyethyl) 6,7 dihydroxy-A-dodecahydrophenanthren-Z-one acetonide, approximately 38 partsby weightof sodium acetate and approximately 38 parts by weight of potassiumacetate. The mixture is melted and heated over a range of about 252282C. at a pressure of about'.0.1 mm. of mercury. After a period of about50 minutes approximately 4.5 parts by weight of distillate is collected,which distillate is then taken up with diethyl ether. Upon cooling thesolution and seeding, approximately 2.9 parts by Weight of whitecrystalline dl-antitrans-l;8a-dimethyl-6,7-dihydroxy Aloamdodecahydrophenanthren-Z-one acetonide is obtained.

Example V distillate is collected, which distillate is taken up with amixture of diethyl ether and petroleum ether and crystallized therefrom.The white crystalline product so obtained is dl-anti-trans-1,8a-dimethyl6,7 dihydroxy- A -dodecahydrophenanthren-Z-one acetonide. The yieldbased upon the distillates is 53.7% .of theory.

Example VI To a suitable reaction vessel equipped with a take-ofl tubeconnected through a vacuum adapter to a recovery vessel is addedapproximately 10.1 parts by weight of the sodium salt of the a-isomer ofdl-anti-trans-1,8a-dimethyll-(fi-carboxyethyl)-6,7-dihydroxy Adodecahydrophenanthren-Z-one acetonide and approximately 100 parts byweight of sodium phenyl acetate. The mixture is melted and heated over arange of about 248-285 C. at a pressure of about 0.10.2 mm. of mercury.After .a period of about 115 minutes approximately 9.7 parts by weightof distillate is collected, which distillate is taken up with a mixtureof diethyl ether and petroleum ether and crystallized therefrom. Thewhite crystalline product is al-anti-trans-1,8a-dimethyl-6,7-dihydroxy-AThe mixture is melted 4 dodecahydrophenanthren-Z-one acetonide. basedupon the distillate is 97% of theory;

The amount of alkali metal salt of a hydrocarbon monocarboxylic acidadmixed with the keto-acid salt may vary widely, as for example from 0.5to parts by weight for each part by weight of the keto acid. salt may beemployed. In general, however, 1 to 10 parts by weight for The yieldeach part by-weight of the keto-acid salt gives optimum results. 7

Although the invention has been described with respect to certainembodiments it is to be understood that it is not so limited and thatvariations and modifications thereof obvious to those skilled in the artmay bemade without departing from the spirit or scope of this invention.

I 2. The process of claim 1 wherein the What is claimed is:

1. In a process for the removal of the fi-carboxyethyl side chain of apolyhydrophenanthrene compound, the step which comprises subjecting analkali metal salt of. an 1,8a-dimethyl-1-(p carboxyethyl) Apolyhydrophenanthren-Z-one of the structure r CH3 CE;

l :R noooomom- H where R is a 4-carbon atom chain linking the 5a and 8acarbon atoms to form a 6-membered fused ring, in the form of a melt to atemperature in the range of about 200 C. to about 350 C. at a pressurebelow atmospheric. 4 pressure is be low about mm. of mercury. I

3. In a process for the removal of the fi-carboxyethyl side chain of apolyhydrophenanthrene compound, "the step which comprises subjecting amolten mixture-ofan alkali metal salt of an1,8a-dimethyl-l-(B-carboxyethyD- A -polyhydrophenanthren-Z-one of thestructure CH3 CH3 I H0.0CCH2CH2- H.

where R is a 4-carbon atom chain linking the 5a and 8a carbon atoms toform a G-membered 'fused ring, said 4- carbon atom chain being selectedfrom the group consisting of CH -CH=CHCH and -CH2CH-CH-CH2 covering 1,8adimethyl-A -polyhydrophenanthren 2- one of the structure where R has thesame siguificance' as above.

4. The process of claim 3 wherein the pressure is below about 100 mm. ofmercury.

5. The process of claim 3 wherein the respective alkali metal salts aresodium salts.

6. The process of removing the ft-carboxyethyl side chain fromanti-trans-1,8a-dirnethyl-l-(B-carboxyethyl)- A-decahydrophenanthren-Zone of the structure CH: CH:

H0.0CCHzCH2- H which comprises subjecting a melt of a mixture of thesodium salt of said acid and the sodium salt of a hydrocarbonmono-carboxylic acid Whose hydrocarbon radical contains from 1 to carbonatoms and is free of olefinic and acetylenic unsaturation to atemperature in the range of about 250 C. to about 320 C. at a pressurebelow about 100 mm. of mercury, collecting the distillate, andrecovering from said distillate anti-trans-1,8a-dimethyl- A'decahydrophenanthren-2-one of the structure CH3 CH:

7. The process of claim 6 wherein the sodium salt of a hydrocarbonmono-carboxylic acid is sodium acetate.

8. The process of removing the ,B-carboxyethyl side chain fromanti-trans-1,8a-dimethyl-1-(fi-carboxyethyh- 6,7 dihydroxy Adodecahydrophenanthren 2 one acetonide of the structure i 0 cm 30.0 0011,011:- H

which comprises subjecting a melt of a mixture of the sodium salt ofsaid acid and the sodium salt of a hydrocarbon mono-carboxylic acidWhose hydrocarbon radical contains from 1 to 10 carbon atoms and is freeof olefinic and '6 acetylenic unsaturation to a temperature in the rangeof about 250 C. to about 320 C. at a pressure below mm. of mercury,collecting the distillate, and recovering from said distillateanti-trans-l,8a-dimethyl-6,7-dihydroxy-A -dodecahydrophenanthren-2 oneacetonide of the structure CH3 CH3 O on;

9. The process of claim 8 wherein the sodium salt of a hydrocarbonmono'carboxylic acid is sodium benzoate.

1G. The process of removing the fi-carboxyethyl side chain fromanti-transl,8a-dimethyl-l-(fi-carboxyethyl)- 6,7 dihydroxy Adodecahydrophenanthren 2 one acetonide of the structure CH3 CH3 CH3 0 fX CH: C H:

CH: O

References Cited in the file of this patent UNITED STATES PATENTSBarkley June 5, 1956 OTHER REFERENCES Woodward, JACS, p. 4224 ff.(1952).

1. IN A PROCESS FOR THE REMOVAL OF THE B-CARBOXYETHYL SIDE CHAIN OF APOLYHYDROPHENANTHRENE COMPOUND, THE STEP WHICH COMPRISES SUBJECTING ANALKALI METAL SALT OF AN 1,8A-DIMETHYL-1-(B-CARBOXYETHYL) -$10-POLYHYDROPHENANTHREN-2-ONE OF THE STRUCTURE